Several viruses assemble their core proteins and genomic material in the cytoplasm of a host cell and exit the cell by budding from the plasma membrane. Studies of these viruses, e.g. HIV-1 viruses, have shown that in addition to proteins encoded by the virus, host cell proteins can be found in viruses. While some of these proteins may be taken into the viruses simply because of their proximity to the viral assembly and budding sites, other host cell proteins are likely to be included in viruses as a result of their interaction with viral proteins during assembly and release. Additionally, some host cell proteins may be incorporated to provide a function for the virus during the infection process. Host cell proteins have been found on the surface or the interior of the viruses. Despite their detection on or in viruses, the role and function of host cell proteins in the viral assembly process is poorly understood and still highly speculative.
A variety of agents are presently used to combat viral infection. These agents include anti-viral compounds, compounds suitable for active immunization such as vaccines and compounds suitable for passive immunization such as neutralizing immunoglobulins. The latter group is often focused on neutralizing immunoglobulins that act through specific binding to viral proteins or cell surface receptors involved in viral entry. Due to their binding specificity, such immunoglobulins are however only suitable in the prophylaxis and/or treatment of specific viral diseases and are not broadly applicable in the treatment of viral diseases.
Neutralization of viruses has been described for immunoglobulins directed against virus-incorporated host cell derived proteins. For instance HIV-1 has been shown to incorporate the host cell derived protein Intercellular Adhesion Molecule-1 (ICAM-1) and an antibody against ICAM-1 has been shown to neutralize ICAM-1 expressing HIV-1 virions (see Rizzuto and Sodroski, 1997). Disadvantageously, ICAM-1 is also localized on the surface of uninfected host cells, so protection and/or treatment of a viral infection with the immunoglobulin against ICAM-1 may, due to interaction of the immunoglobulin with uninfected host cells, result in serious and unwanted side effects. A further disadvantage of the anti-ICAM-1 immunoglobulin is that its neutralizing activity is, similar to the viral protein-specific and cell surface receptor-specific immunoglobulins, virus (HIV-1) specific. Accordingly, there is an urgent need for immunoglobulins that do not have the above-described disadvantages.
The present invention provides such immunoglobulins. The immunoglobulins found are capable of binding an intracellular host cell protein which is incorporated into viruses or expressed at the cell surface. Due to the intracellular localization of the protein in uninfected host cells no unwanted side effects occur upon administration of the immunoglobulins. A further advantage of the immunoglobulins is that they are not dependent on specific viral identification and that they interact with a host cell protein that is commonly involved in the viral assembly and budding process and consequently is capable of neutralizing several distinct viruses.